The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer.
Various surface molecules undergo regulated cleavage by the disintegrin and metalloproteinases ADAM10 and ADAM17. The list of substrates includes molecules involved in brain pathology, inflammation and cancer. In the brain both proteases mediate neuroprotective cleavage events such as inactivation of amyloid precursor protein. In inflammatory settings signaling of cytokines including TNFalpha and IL-6 is triggered by proteolytic release of soluble agonists and leukocyte recruitment is controlled by the cleavage of adhesion molecules. Moreover, in tumors, ADAM10- and ADAM17-mediated shedding events trigger proliferative signaling via activation of growth factors including ErbB family members. Concepts of either increasing ADAM10- or ADAM17-activity to limit neurodegeneration or suppressing their activity to block inflammation or tumor growth have to be carefully scrutinized for their potential side effects in various tissues and pathologies.
Pruessmeyer
Jessica
J
Institute for Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany.
Ludwig
Andreas
A
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000503:physiopathology*; D011480:Protease Inhibitors / Q000494:pharmacology
D008565:Membrane Proteins; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human